Gel containing pirfenidone

ABSTRACT

The invention relates to a gel composition containing pirfenidone, which is advantageous over other cutaneously administered pharmaceutical forms known in the prior art and which can be used in treatment for the restoration of tissues with fibrotic lesions and for the prevention of fibrotic lesions.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent application Ser. No. 15/435,494 (allowed), filed on Feb. 17, 2017, which is a divisional application of U.S. patent application Ser. No. 13/893,626, filed on May 14, 2013, which is a divisional application of U.S. patent application Ser. No. 12/673,304, filed on Apr. 28, 2010 (now U.S. Pat. No. 8,492,412), which claims the benefit of and which is a national stage filing of International Application Serial No. PCT/MX2008/000107, filed on Aug. 14, 2008, which claims priority to, and the benefit of, Mexican Patent Application Serial No. MX/a/2007/009796, filed on Aug. 14, 2007, the entire contents of both of which are hereby incorporated by reference.

FIELD OF INVENTION

The present invention is related to a gel formula that contains Pirfenidone, which offers advantages over other pharmaceutical forms of known cutaneous administration in the state of the technique.

BACKGROUND OF THE INVENTION

The 5-methyl-l-phenyl-2(1H)-pyridone, formula;

It is a drug that has been applied in the restoration of tissues with lesions with fibrosis and the prevention of fibrotic lesions. This compound, Pirfenidone, it is by itself a known compound and its pharmacological effects has been described, for example, in Japanese applications numbers 87677/1974 and 1284338/1976, as an anti-inflammatory agent that includes antipyretic and analgesics. The U.S. Pat. No. 3,839,346, published Oct. 1^(st) of 1974; the U.S. Pat. No. 3,974,281, published august 10^(th) of 1976; the U.S. Pat. No. 4,042,699 published august 16^(th) of 1977, and the U.S. Pat. No. 4,052,509 published Oct. 4^(th) of 1977, which described the methods for the obtained Pirfenidone, as well as its use as an anti-inflammatory agent. In the Mexican patent 182, 266 the antifibrotic activity of the 5-methyl-1-phenyl-2(1H)-pyridone is described.

Different resources and treatments have been used to the date and none of them have shown to be really effective. Pirfenidone has shown its efficacy as an anti-fibrotic agent in different pathologies and organs, and has been demonstrated in previous works, where we have observed an effect on the fibroblasts and the production of collagen and extracellular matrix, as well as in experimental models and in clinical tests also.

Many substances could form gels when a gelificant agent is added. This is use in many diverse products in the manufacturing industry, from food to paint, passing through adhesives.

Gels are also important in the chemistry part related with the processes SOL_GEL and in the synthesis of solid materials with nanopores.

Gels are classified in: aqueous (hydrogels) or organic (organogels), dependingo if the aqueous component is water or an organic solvent; organic or inorganic in nature, colloidal or thick grain, according to the size of the particles; and rigid gels, elastic or tixothrophic, according to its mechanic properties.

The hydrocolloids are substances that are produced from vegetable and animal proteins or multiple sugars. They have the capacity to swell themselves and to bind to water. The hydrocolloids are used to thicken, solidify and stabilize food.

OBJECT OF THE INVENTION

The object of the present invention is to provide a gel composition for its cutaneous administration that contains Pirfenidone, a viscous agent; a solubilizer; a non ionic solubilizer; a conserving agent; a neutralizer agent and purified water.

Also, it is the object of the present invention to provide a process of manufacture of a gel that contains pirfenidone for its cutaneous application.

Another objective of the present invention is to provide a gel medicine to be used as an anti-fibrotic and anti-inflammatory agent.

SPECIFICATION OF THE INVENTION Composition of the Gel

The composition of the gel contains from 2 to 12% of Pirfenidone is elaborated utilizing from 0.4 to 1.2% of a viscous agent, from 10 to 30% of a solubilizer, from 5 to 15% of a non ionic solubilizer, from 0.2 to 1% of a conserving agent, from 0.4 to 1.2% a neutralizer agent and the rest of purify water. The viscous agent is selected from a carbomer 940 (MR); Ultrex 10(MR), cellulose derivatives; gums; polioxameres; ethylic alcohol and propylenglycol; the conserving agent is selected from a group that consist of Diazolidinyl urea, iodopropinil-butilcarbamate; methylparabene and a mix of these compounds; the neutralizer agent is selected from a group of primary, secondary and tertiary aliphatic amines of the mono- , bi- and triethanolamine type, and of the hydroxide alkaline metals, such as sodium hydroxide.

An example of the composition of the gel is shown in the table 1:

Component Quantity (g) % Pirfenidone 8 8 Viscous agent 0.5 0.5 Solubilizer 20 20 Non ionic solubilizer 11.5 11.5 Conserving agent 0.5 0.5 Neutralizer 0.5 0.5 Purified water up to 100 59

The gel containing Pirfenidone is manufactured as follows:

-   -   a) Mix 50% of the total water to be used with the viscous agent,         allowing the complete humectation of the viscous agent;     -   b) Mix separately and with constant agitation the Pirfenidone         with the solubilizer agent;     -   c) Dissolve separately the non ionic solubilizer agent in the         25% water to be used at 40° C., once dissolved, the 15% of the         total water is added;     -   d) Add the solution from part c) to the mix from part b),         agitate until the mix is homogenate.     -   e) Dilute the neutralizer agent in 10% of the total water to         use, agitate until the mix is homogenate; and     -   f) Add with constant agitation and homogenate in each addition         to the mix from part a) the solution from part d); the         conservative and the solution from part e).

A prepared composition according to procedure describe is shown in table 2.

Component Quantity (g) Pirfenidone 8 Carbomer 0.5 N-methylpirrolidone 20 Macrogolglycerol 11.5 Hidroxiestearate 40 Diazolidinilurea and 0.5 Iodopropinil-butilcarbamate Triethanoalamine 0.5 Purified water up to 100 These compositions are shown in an example mode, but they are not limited in any level of the reach of the description of the present invention. 

1. A method of making a composition of a Pirfenidone gel, comprising the following steps: a) mixing 50% of the total water to be used with a viscous agent and allowing complete humectation of the viscous agent; b) mixing Pirfenidone and a solubilizer agent separately and with constant agitation; c) dissolving separately a non ionic solubilizer agent in 25% of total water at 40° C. and once dissolved, adding 15% of total water; d) adding the solution from part c) to the mix from part b), and agitating until homogenous; e) diluting a neutralizer agent in 10% of total water to be used, and agitating until homogenous; and f) combining the solutions of subparts (a)-(e).
 2. A method for treating fibrotic lesions in a patient by administering to the patient a composition of Pirfenidone gel consisting of 8% Pirfenidone, 0.5% of a viscous agent, 20% of a solubilizer, 11.5% of a non ionic solubilizer, 0.5% of a conserving agent, 0.5% of a neutralizer agent and 59% of purified water, thereby treating the fibrotic lesions.
 3. The method of claim 2, wherein (a) the viscous agent is selected from the group consisting of a Carbomer 940 (MR), Carbomer Homopolymer Type A, a cellulose derivative, a gum, and a poloxamer; (b) the solubilizer is selected from the group consisting of N-methylpyrrolidone, ethyl alcohol, and propylene glycol; (c) the conserving agent is selected from the group consisting of diazolidinyl urea, iodopropynyl butylcarbamate, methylparaben, propylparaben, and mixes of these conserving agents; and (d) the neutralizer agent is selected from the group consisting of primary, secondary and tertiary mono-, bi-, and triethanolamine aliphatic amines, and a hydroxide alkaline metal.
 4. The method of claim 3, wherein the viscous agent is Carbomer 940 (MR), the solubilizer is N-methylpyrrolidone, the conserving agent is diazolidinyl urea, and the neutralizer agent is triethanolamine.
 5. The method of claim 3, wherein the viscous agent is Carbomer 940 (MR), the solubilizer is N-methylpyrrolidone, the conserving agent is iodopropynyl butylcarbamate, and the neutralizer agent is triethanolamine.
 6. The method of claim 3, wherein the hydroxide alkaline metal is sodium hydroxide. 